tbuckley/cabot-search huggingface dataset:
Abstract 5303: Upregulation of the polycomb group protein SCML2 contributes to aggressive prostate cancer
Authors: Ava M. Boston, Abdulrahman M. Dwead, Marwah M. Al-Mathkour, Kezhan Khazaw, Bekir Cinar
Journal: Cancer Research (2023)

Abstract Advanced prostate cancer (PC) is the leading cause of death in the US because there is no effective treatment due to the poorly understood disease mechanism. Sex comb on midleg-like-2 (SCML2) is a member of Polycomb repressive complex 1 and regulates homeotic gene expression during development. Using proteomic approaches, we have identified SCML2 as a binding partner of the YAP1 protein complexes isolated from PC cell lines. Both SCML2 and YAP1 regulate basic cellular biology, including stem cell maintenance and carcinogenesis; however, whether SCML2 and YAP1 cooperate to contribute to the aggressive PC in humans remains unknown. We showed that AR-positive cell lines express high levels of SCML2 with a significant increase in castration-resistant PC cells compared to its castration-sensitive cell counter, suggesting a possible role of SCML2 in PC progression. We also showed that androgens regulated the protein-protein interaction between SCML2 and YAP1, as evaluated by proximity ligation assay. In addition, the GST-pulldown assay revealed that SCML2 interacted with the WW/SH3 domain of YAP1, where AR also binds. Besides, our RNAi-aided gene silencing experiment demonstrated that YAP1 and SCML2 might be functionally antagonistic. Moreover, gene silencing and growth assays showed that SCML2 might act as a growth suppressor in castration-sensitive PC cells while acting as a growth mediator or survival factor in castration-resistant PC cells. Furthermore, our analysis of the cancer genome atlas PC data set has indicated that amplification of SCML2 is associated with reduced progression-free survival. These observations suggest that SCML2 and YAP1 interaction is biologically functional, and the degree of their interaction may play a critical role in PC progression downstream of dysregulated androgen/AR signaling. Citation Format: Ava M. Boston, Abdulrahman M. Dwead, Marwah M. Al-Mathkour, Kezhan Khazaw, Bekir Cinar. Upregulation of the polycomb group protein SCML2 contributes to aggressive prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5303.
Abstract 5353: Graph representation learning of tumor topology from spatial imaging data
Authors: Nicholas Ceglia, Samuel S. Freeman, Maryam Pourmaleki, Andrew McPherson, Sohrab P. Shah
Journal: Cancer Research (2023)

Abstract Recently, novel technologies have enabled spatially resolved multiplexed protein profiling of tumors; however, there is an unmet need for unbiased detection of spatial structures within the tissue. By encoding multiplexed images as a graph, we produce an efficient and well-studied graph representation that allows for the application of sophisticated machine learning methods, particularly graph neural networks (GNNs) and graph autoencoders (GAE). While GNNs have recently become popular tools in the analysis of spatial data, current GNN methods are limited by production of cell-level representations rather than graph-level representations. To understand patterns of local tissue structure and protein expression, we implemented a generalizable GAE framework that summarizes marker intensity and morphological values with the local topology of neighboring cells. In this way, each local cellular graph is represented as a single point in the lower dimensional space. We show that our framework generates low-dimensional features that reflect both cellular attributes and tissue structure. We demonstrate that clustering local structure in 318 fields of view from 22 tumor lesions across 7 patients with in-transit melanoma captured using multiplexed immunofluorescence (mpIF) can produce spatial motifs predictive of response to intralesional interleukin-2 (IL-2) immunotherapy. Additionally, we applied our framework to mpIF data of 146 high grade serous ovarian cancer tumors across 50 patients. We identify clusters with higher CD8+ T cell infiltration that associate with homologous recombination deficiency. Our method can be readily applied to various spatially resolved multiplexed imaging platforms, and the resulting embeddings provide a compressed representation of subgraphs that can be used in further classification or regression analysis of patient- and/or image-level histological, clinical, or genomic labels. Citation Format: Nicholas Ceglia, Samuel S. Freeman, Maryam Pourmaleki, Andrew McPherson, Sohrab P. Shah. Graph representation learning of tumor topology from spatial imaging data. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5353.
Abstract 3344: Early detection biomarkers of LncRNA H19 genotypes for determining childhood leukemia susceptibility
Authors: Chia-Wen Tsai, Wen-Shin Chang, Chao-Chun Chen, Pei-Chen Hsu, Yun-Chi Wang, Jen-Sheng Pei, Da-Tian Bau
Journal: Cancer Research (2023)

Abstract The purpose of our study was to investigate whether genetic variations in lncRNA H19 were associated with susceptibility to childhood leukemia. 266 childhood leukemia patients and 266 healthy controls were enrolled in Taiwan, and two single nucleotide polymorphisms (SNPs), rs2839698 and rs217727, in H19 were genotyped and analyzed. There was a significant difference in the genotypic distribution of rs2839698 between patients and healthy controls (p=0.0277). Compared to the wild-type CC genotype, the heterozygous variant CT and homozygous variant TT genotypes were associated with significantly increased risks of childhood leukemia with an adjusted odds ratio (OR) of 1.46 (95% confidence interval [CI], 1.08-2.14, p=0.0429) and 1.94 (95%CI, 1.15-3.31, p=0.0169), respectively (p for tread=0.0277). The difference in allelic frequencies between childhood leukemia patients and controls was also significant (T versus C, adjusted OR = 1.53, 95%CI, 1.13-1.79, p=0.0077). There were no significant differences in the genotypic and allelic distributions of rs217727 between cases and controls. Our results indicated that H19 SNP rs2839698, but not rs217727, may serve as a novel susceptibility marker for childhood leukemia. Citation Format: Chia-Wen Tsai, Wen-Shin Chang, Chao-Chun Chen, Pei-Chen Hsu, Yun-Chi Wang, Jen-Sheng Pei, Da-Tian Bau. Early detection biomarkers of LncRNA H19 genotypes for determining childhood leukemia susceptibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3344.
Abstract 4894: The anti-ROR1 ADC STRO-003 demonstrates immune-modulating properties that may enhance checkpoint blockade
Authors: Alice Yam, Helena Kiefel, Andrew McGeehan, Robert Yuan, Sihong Zhou, Dayson Moreira, Indrani Dutta, Xiaofan Li, Cuong Tran, Gang Yin, Kristin Bedard, Trevor Hallam
Journal: Cancer Research (2023)

Abstract There is growing evidence that tumor-targeted cytotoxins can also enhance anti-tumor immunity by inducing immunogenic cell death (ICD) in tumor cells and promoting recruitment of immune effector cells. We sought to investigate the immune stimulating potential of STRO-003, an antibody drug conjugate (ADC) composed of an anti-Receptor Orphan Receptor Kinase 1 (ROR1) antibody conjugated to a topoisomerase I targeted exatecan warhead via a cleavable linker. ROR1 is an oncofetal transmembrane receptor with restricted expression in normal tissues. Its overexpression in several cancer indications has been described, including in ovarian, non-small cell lung carcinoma (NSCLC), triple negative breast cancer (TNBC), and hematological malignancies, thus making it an ideal ADC target. We have previously demonstrated potent in vivo activity of STRO-003 in a panel of ROR1-expressing lung cancer patient-derived xenograft (PDX) models. Here we show that the exatecan warhead, SC3386, and STRO-003 ADC induced ICD in vitro as evidenced by presentation of cell-surface calreticulin and release of HMGB1. Consistent with this finding, STRO-003-treated cells elicited monocyte activation in a PBMC co-culture assay. To determine if these immunogenic properties could improve therapeutic efficacy, we evaluated STRO-003 in combination with an immune checkpoint inhibitor in a mouse syngeneic model expressing ROR1. We have demonstrated that STRO-003 in combination with checkpoint inhibition significantly enhances efficacy in a syngeneic mouse model and supports durable anti-tumor immunity. Follow-up vaccination studies were performed to further explore the significance of STRO-003-induced ICD and protective immunity in vivo. These results demonstrate that tumor cells pre-treated with STRO-003 or SC3386 undergo potent immunogenic cell damage which can, in turn, mount protective immunity in vivo. Citation Format: Alice Yam, Helena Kiefel, Andrew McGeehan, Robert Yuan, Sihong Zhou, Dayson Moreira, Indrani Dutta, Xiaofan Li, Cuong Tran, Gang Yin, Kristin Bedard, Trevor Hallam. The anti-ROR1 ADC STRO-003 demonstrates immune-modulating properties that may enhance checkpoint blockade. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4894.
Abstract 3730: A new type of transcriptional reprogramming by an IRF4 mutation in lymphoma
Authors: Pierre Cauchy
Journal: Cancer Research (2023)

Abstract Disease-causing mutations in genes encoding transcription factors (TFs) are a recurrent finding in hematopoietic malignancies and might involve key regulators of lineage adherence and cellular differentiation1-3. Such mutations can affect TF-interactions with their cognate DNA-binding motifs4,5. Whether and how TF-mutations impact upon the nature of binding to TF composite elements (CE) and influence their interaction with other TFs is unclear. Here, we report a new mechanism of TF alteration in human lymphomas with perturbed B cell identity. It is caused by a recurrent somatic missense mutation c.295T&amp;gt;C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cell-differentiation and -activation6,7. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF composite elements (CEs). Furthermore, IRF4-C99R thoroughly modifies IRF4 function, by blocking IRF4-dependent plasma cell induction, and up-regulating disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single arginine mutation creates a complex switch of TF specificity and gene regulation. These data open the possibility of designing specific inhibitors to block the neomorphic, disease-causing DNA-binding activities of a mutant transcription factor. Citation Format: Pierre Cauchy. A new type of transcriptional reprogramming by an IRF4 mutation in lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3730.
Abstract 1378: Proguanil inhibits breast cancer <i>in vitro</i> and <i>in vivo</i> through mitochondrial dysfunction
Authors: Marina Curcic, Nehal Gupta, Sanjay K. Srivastava
Journal: Cancer Research (2023)

Abstract Breast cancer remains the second leading cause of cancer-related death among women in the U.S. New treatments for this aggressive disease are thus urgently needed. Repurposing FDA-approved non-cancer drugs for cancer treatment is an alternative that saves time and lowers the costs needed for drug development. In this study, we investigated the effects of proguanil, an anti-malarial drug, in breast cancer cells. Proguanil exhibited a significant cytotoxic effect on various breast cancer cell lines including patient derived cell lines through induction of apoptosis. Our results indicated that proguanil treatment caused a 3-fold increased production of ROS compared with control and reduced the mitochondrial membrane potential, mitochondrial respiration rate, and ATP production. Our studies also revealed the phosphorylation of H2AX, a marker for DNA damage. Proguanil treatment further increased the expression of apoptotic markers Bax, cleaved PARP, cleaved-caspase 9, and down-regulated anti-apoptotic Bcl-2 and survivin in breast cancer cells. Oral administration of 20mg/kg of proguanil significantly inhibited the tumor growth by 55% in mice model. Western blot analyses of tumors from proguanil-treated group showed increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 compared to control. Taken together, our results demonstrate the anti-cancer effect of proguanil by targeting mitochondria, and can be considered for clinical investigation against breast cancer. Citation Format: Marina Curcic, Nehal Gupta, Sanjay K. Srivastava. Proguanil inhibits breast cancer in vitro and in vivo through mitochondrial dysfunction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1378.
Abstract 4585: Tumor lymphangiogenesis sensitizes melanomas to the immunological effects of radiotherapy but also disrupts the local lymphatic vasculature
Authors: Anish Mukherjee, Nikolaos Mitrousis, Mari Stella Sasso, Margo MacDonald, Ainhoa Arina, Phillip Ang, Ariana Baginski, J. Emiliano G. Medellin, Ralph R. Weichselbaum, Melody A. Swartz
Journal: Cancer Research (2023)

Abstract Tumor lymphangiogenesis is typically associated with cancer progression and metastasis. However, recent studies from our group have demonstrated that tumor lymphangiogenesis promotes intratumor T cell infiltration and potentiates the efficacy of a wide range of immunotherapies in melanoma-bearing mice as well as patients undergoing checkpoint blockade. Radiotherapy (RT) can also induce immunogenic tumor cell death, so we investigated whether lymphangiogenic tumors would yield more immunogenic responses to RT than non-lymphangiogenic tumors. Here, we compared effects of RT in mice bearing B16-F10 melanomas expressing either a control vector (B16-Ctrl) or overexpression the lymphangiogenic factor VEGF-C (B16-VC), where lymphatic vessels were significantly increased in number and size compared to B16-Ctrl tumors. First, we find that B16-VC regress faster than B16-CT after RT (either a single 20 Gy dose or two 15 Gy doses), and that this regression was correlated with enhanced CD8+ T cell activity. On the other hand, lymphatic endothelial cells (LECs) can be more sensitive to damage from RT if they are undergoing lymphangiogenesis. We found that irradiated B16-VC tumors showed higher levels of intra-lymphatic fibrin. Consistent with this, LECs in the irradiated B16-VC tumors expressed higher levels of tissue factor and caspase-3, which correlated with the degree of lymphatic clotting. Fibrin clotting was also observed in the subcapsular sinus of the draining lymph nodes of irradiated B16-VC tumors. These findings highlight the complex role of tumor lymphangiogenesis in radiotherapy responses, where they may potentiate acute anti-tumor immune responses but may also cause localized damage of the vasculature, potentially leading to increased metastasis. Further studies are needed to investigate therapeutic targets to inhibit lymphatic coagulation and look at its effects on cancer immunotherapy and metastasis. Citation Format: Anish Mukherjee, Nikolaos Mitrousis, Mari Stella Sasso, Margo MacDonald, Ainhoa Arina, Phillip Ang, Ariana Baginski, J. Emiliano G. Medellin, Ralph R. Weichselbaum, Melody A. Swartz. Tumor lymphangiogenesis sensitizes melanomas to the immunological effects of radiotherapy but also disrupts the local lymphatic vasculature. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4585.
Abstract 309: ATM phosphorylation of NRF2 promotes DNA damage repair
Authors: Cheyenne A. Schneider, Tin-Yu Lin, Aimee Falzone, Samantha Caldwell, Jared L. Johnson, Gina M. DeNicola
Journal: Cancer Research (2023)

Abstract Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that responds to cellular and oxidative stress by promoting the transcription of antioxidant response element-containing genes. In an unstressed cellular environment, NRF2 is bound by Kelch-like ECH-associated protein 1 (KEAP1) and tagged for proteasomal degradation. In many cancers, the interaction between NRF2 and KEAP1 is interrupted due to mutations in either protein. Previous work has suggested that NRF2 can promote DNA damage repair, and our preliminary data demonstrates that NRF2 is phosphorylated at Serine-40 by the DNA damage response kinase, Ataxia Telangiectasia Mutated (ATM) in response to DNA damage. To create a system to better study the relationship between NRF2 Serine-40 phosphorylation and DNA damage, we modified the mouse Nfe2l2 locus to generate a mouse model in which Nrf2 Serine-40 is mutated to Alanine on a C57BL/6 background. Utilizing this model, we administered 7.5 Gy of total body irradiation and found that Nrf2S40A/S40A mice had significantly shortened survival compared to Nrf2WT mice. Immunohistochemical analysis of radiation-sensitive tissues including bone marrow and spleen revealed a prolonged persistence of the DNA damage marker γH2AX following irradiation in the Nrf2S40A/S40A group compared to Nrf2WT. We also observed a significantly higher level of cell death in the Nrf2S40A/S40A splenic tissue compared with Nrf2WT as indicated by the marker of apoptotic cell death, Cleaved Caspase-3. Our findings indicate that phosphorylation of Nrf2 at Serine-40 in response to DNA damage promotes DNA damage repair. Our ongoing work is focused on examining these phenotypes in cellular systems to determine the specific mechanisms by which NRF2 promotes DNA damage repair. Future work will include incorporating the systems generated thus far into non-small cell lung cancer (NSCLC) and liver cancer mouse models to further investigate the impact of this phosphorylation site on tumorigenesis and radio-resistance. Citation Format: Cheyenne A. Schneider, Tin-Yu Lin, Aimee Falzone, Samantha Caldwell, Jared L. Johnson, Gina M. DeNicola. ATM phosphorylation of NRF2 promotes DNA damage repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 309.
Abstract 4591: Mechanisms of tumor-mediated endothelial cell proliferation independent of VEGF
Authors: Kevin L. Sheng, Jude Raj, Kris C. Wood
Journal: Cancer Research (2023)

Abstract A hallmark of cancer is dysregulated angiogenesis and blood vessel co-option, which are often driven by vascular endothelial growth factor (VEGF). Despite the key role of VEGF signaling in promoting endothelial cell (EC) proliferation, survival, and migration, the clinical use of VEGF inhibitors has modest success and faces many challenges. In particular, patients demonstrate variable initial responses to anti-VEGF therapy, and many of those who respond to treatment subsequently develop resistance. These challenges suggest that there may be VEGF-independent mechanisms driving EC proliferation in the tumor microenvironment. To study these mechanisms, we established an in vitro model using a dual-reporter system in a co-culture model of ECs and tumor cells. Specifically, we used an immortalized endothelial cell line (SVEC4-10) expressing GFP and Renilla luciferase and a mouse renal carcinoma cell line (RENCA) expressing Tomato and Firefly luciferase. This model allowed us to independently evaluate the growth rates and cell viabilities of both ECs and tumor cells in direct co-culture. Our preliminary data revealed that ECs exhibit increased growth rates when directly co-cultured with tumor cells. Interestingly, this EC proliferation is VEGF-independent and not impacted by VEGF-A knockout in tumor cells or with treatment of a pan-VEGFR small molecule inhibitor (axitinib). To further characterize if our phenotype was due to other tumor secreted factors, we used a transwell setup to eliminate direct contact between ECs and tumor cells and found that EC growth rates were substantially mitigated. These results revealed that tumor cells induced EC proliferation through a physical cell-to-cell interaction that is independent of VEGF. Further characterizing this unknown mechanism may inform therapeutic interventions to overcome the clinical challenges of anti-VEGF therapies for cancer. To expand our understanding of this VEGF-independent EC proliferation, we aim to characterize the cell surface proteome from tumor-conditioned ECs using cell surface mass spectrometry. We will validate hits from this study using our in vitro model and translate these findings to in vivo mouse models. We expect that our current and future research will reveal new insights into tumor co-option of the vascular system and identify novel targets for developing therapies to effectively treat cancer. Citation Format: Kevin L. Sheng, Jude Raj, Kris C. Wood. Mechanisms of tumor-mediated endothelial cell proliferation independent of VEGF. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4591.